U.S. patent application number 17/122470 was filed with the patent office on 2021-06-24 for pipetting device and method.
This patent application is currently assigned to TECAN TRADING AG. The applicant listed for this patent is TECAN TRADING AG. Invention is credited to Thomas Geiges, Michael KELLER.
Application Number | 20210187493 17/122470 |
Document ID | / |
Family ID | 1000005292474 |
Filed Date | 2021-06-24 |
United States Patent
Application |
20210187493 |
Kind Code |
A1 |
KELLER; Michael ; et
al. |
June 24, 2021 |
PIPETTING DEVICE AND METHOD
Abstract
Pipetting device for pipetting a liquid driven by a gaseous
working medium, the pipetting device having at least one pipette
connector adapted to attach a pipette at a connection opening at
least one pressurizing and/or suctioning pressure source, a gas
flow connection between said connection opening and at least one
pressure source, a flow restriction defining at least a section of
said gas flow connection, a first sensor configured to measure a
quantity indicative of the temperature of the flow restriction. The
invention is further directed to a gas flow connection element for
a pipetting device and to a method of pipetting a liquid
volume.
Inventors: |
KELLER; Michael; (Bauma,
CH) ; Geiges; Thomas; (Mannedorf, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TECAN TRADING AG |
Mannedorf |
|
CH |
|
|
Assignee: |
TECAN TRADING AG
Mannedorf
CH
|
Family ID: |
1000005292474 |
Appl. No.: |
17/122470 |
Filed: |
December 15, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01L 2400/06 20130101;
B01L 2300/1888 20130101; B01L 2400/0487 20130101; B01L 2300/14
20130101; B01L 3/021 20130101; B01L 2200/147 20130101 |
International
Class: |
B01L 3/02 20060101
B01L003/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2019 |
EP |
19 217 577.6 |
Claims
1. Pipetting device (10) for pipetting a liquid driven by a gaseous
working medium, the pipetting device comprising: at least one
pipette connector (13) adapted to attach a pipette (21) at a
connection opening (14), at least one pressurizing and/or
suctioning pressure source (11, 11', 11''), a gas flow connection
(12) between said connection opening and said at least one pressure
source, a flow restriction (15) defining at least a section of said
gas flow connection, a first sensor (16) configured to measure a
quantity indicative of the temperature of the flow restriction.
2. Pipetting device (10) according to claim 1, further comprising a
time controller (17) operatively connected to a controllable valve
(18, 18', 18'', 18'''), which controllable valve is configured to
selectively open or interrupt said gas flow connection (12) in a
time-controlled manner.
3. Pipetting device (10) according to claim 1, further comprising a
heat storage block (19), wherein the flow restriction (15) is
formed by an inner wall of the heat storage block or wherein the
flow restriction (15) is formed by a flow restriction element (15')
embedded in the heat storage block, and wherein said first sensor
(16) is a temperature sensor thermally connected to said heat
storage block.
4. Pipetting device (10) according to claim 3, wherein said heat
storage block (19) comprises a metal, in particular wherein said
heat storage block comprises sintered metal, in particular, wherein
said heat storage block consists of a monolithic sintered metal
structure.
5. Pipetting device (10) according to claim 3, wherein the flow
restriction (15) is formed by an inner wall of the heat storage
block and wherein said inner wall is the wall of at least a section
of a through hole through the heat storage block, in particular of
a through hole formed by mechanical drilling, formed by laser
drilling or formed by an additive manufacturing method.
6. Pipetting device (10) according to claim 3, wherein the flow
restriction (15) is formed by a flow restriction element (15')
embedded in the heat storage block wherein a wall of said flow
restriction element (15') consists of a first material having a
first specific thermal conductivity, wherein said heat storage
block (19) consists of a second material having a second specific
thermal conductivity, and wherein said second specific thermal
conductivity is higher than said first specific thermal
conductivity.
7. Pipetting device (10) according to claim 6, wherein said flow
restriction element (15') is formed as a tubular capillary, in
particular a glass capillary, in particular made from fused silica,
which tubular capillary extends through a cavity (41) formed in
said heat storage block (19).
8. Pipetting device (10) according to claim 7, wherein an inner
surface of said cavity is arranged such that thermal radiation can
be exchanged with an outer surface of said tubular capillary and/or
wherein an inner surface of said cavity is in thermally conducting
contact with an outer surface of said tubular capillary and/or
wherein said cavity is partially or completely filled with a
material having a specific thermal conductivity of at least the
specific thermal conductivity of said tubular capillary, in
particular filled with thermally conducting glue.
9. Pipetting device (10) according to claim 3, said pipetting
device comprising a multiplicity of connection openings (14), a
multiplicity of gas flow connections (12) between each of said
connection openings and said at least one pressure source (11, 11',
11''), and a multiplicity of flow restrictions (15) each defining
at least a section of one of said gas flow connections of said
multiplicity of gas flow connections, wherein all of said flow
restrictions (15) of said multiplicity of flow restrictions are
embedded in said heat storage block (19).
10. Pipetting device (10) according to claim 3, wherein said heat
storage block (19) further accommodates at least an electrically
operated valve, in particular said controllable valve (18, 18',
18'', 18''').
11. Gas flow connection element (20) for a pipetting device (10)
according to claim 3, said gas flow connection element comprising:
said flow restriction (15), said heat storage block (19), and said
temperature sensor (16) being thermally connected to said heat
storage block and/or to said flow restriction.
12. Method (100) of pipetting a liquid volume (22) of a liquid by
driving said liquid by means of a gaseous working medium, said
method comprising the steps of a) providing (101) a pipetting
device according to claim 1; b) defining (102) a volume of liquid
to be pipetted and defining whether pipetting is aspirating or
dispensing; c) reading (103) a value from said first sensor (16);
d) determining (104) a temperature of said flow restriction (15) as
function of at least said value read from said first sensor (16);
e) determining (105) at least one pipetting parameter as a function
of said volume of liquid to be pipetted and of said temperature
determined in step d); f) operating (106) said pipetting device by
applying said at least one pipetting parameter determined in step
e), which operating involves flowing of an amount of said gaseous
working medium across said flow restriction (15), thereby pipetting
said liquid volume.
13. Method (100) according to claim 12, wherein said pipetting
device (10) is a pipetting device, wherein said at least one
pipetting parameter determined in step e) is an opening time
(.DELTA.t) of said controllable valve, and wherein operating said
pipetting device comprises the partial steps f1) starting (107)
pipetting of said liquid volume by opening said at least one valve
during said opening time determined in step e); and f2) closing
(108) said controllable valve after said opening time (.DELTA.t)
has elapsed.
14. Method according to claim 13, wherein said opening time
(.DELTA.t) is controlled by open-loop control.
15. Method according to claim 13, wherein said opening time
(.DELTA.t) is determined further in function of at least one of an
ambient temperature (.theta..sub.a), an ambient pressure (p.sub.a),
calibration data indicative for a switching time of said
controllable valve, a parameter or a set of parameters defining a
geometric property of the flow restriction, in particular a cross
section area of the flow restriction, a length of the flow
restriction, or a flow resistance of the flow restriction for a
fluid having a defined viscosity, a temperature dependence of the
viscosity of said gaseous working medium.
Description
[0001] The invention addressed herein relates to a pipetting
device, more specifically to a pipetting device for pipetting a
liquid driven by a gaseous working medium. Under further aspects,
the invention relates to a gas flow connection element for a
pipetting device and to a method of pipetting a liquid volume.
[0002] In the field of liquid handling, it is common practice to
use pipettes to aspirate and dispense a liquid. Such a liquid may
e.g. be a chemical product or a sample of a bodily fluid. One type
of pipetting devices is the so-called air displacement pipette.
When using this type of pipette, a defined volume of a gaseous
working medium, in typical cases air, is loaded into the pipette or
removed from the pipette. Thereby a pressure on one side of the
liquid in the pipette or adjacent to an opening of the pipette is
decreased or increased with respect to reference pressure, such
that a force results, which drives the liquid out of the pipette or
into the pipette. We understand throughout the present description
and claims under "a pipette" a tubular member with one opening for
aspiration and release of a liquid product dose and in addition,
with a second opening. The second opening can be brought in contact
with the gaseous working medium having under-pressure to achieve
aspirating of a liquid through the first opening or can be brought
in contact with the gaseous medium having over-pressure to achieve
dispensing of a liquid from the inside of the pipette through the
first opening. Under-pressure and over-pressure are defined in
relation to an ambient pressure and can be applied in a controlled
way.
[0003] In fields as for example pharmaceutical research, clinical
diagnostics and quality assurance, highly automated facilities for
the handling, processing and analyzing of liquids are in use. In
such facilities, pipetting devices often play a central role in
producing liquid doses of a predetermined amount and in
transporting doses of liquid between different stations for
processing or for analyzing the liquid. Accuracy and precision of
the produced liquid doses is of large importance. In general, rapid
processing is desired. This can be achieved by parallel handling of
liquid doses or by applying fast repetition rates. Furthermore, it
is important to keep accuracy and precision over extended time on a
high level, in particular in long sequences of similar pipetting
operations, pipetting operations performed in the beginning of the
sequence should not lead to different results than pipetting
operation performed at the end of the sequence. Liquid doses
produced with individual pipette tips of the same type and nominal
dimension should only have minimal variance.
[0004] EP 2 412 439 A1 discloses a pipetting device having a flow
restriction in the path of a gaseous working medium, which flow
restriction is dimensioned such that the flow resistance of the
working medium in the flow restriction is significantly lower than
the flow resistance of the liquid passing the opening of the
pipette. This leads to a reduction of the susceptibility to
variations of the pipette tips, e.g. to variations in the exact
diameter of the orifice of the pipette tips.
[0005] The object of the present invention is to provide an
alternative pipetting device for pipetting a liquid driven by a
gaseous working medium. A further object of the invention is to
provide a device and a method, which improve at least one of
accuracy, precision and temporal stability of pipetting, i.e. at
least one of aspirating or dispensing, a liquid driven by a gaseous
working medium.
[0006] This object is achieved by a pipetting device according to
claim 1. The pipetting device according to the invention is a
pipetting device for pipetting a liquid driven by a gaseous working
medium.
[0007] The pipetting device comprises at least one pipette
connector adapted to attach a pipette at a connection opening.
[0008] The pipetting device comprises at least one pressurizing
and/or suctioning pressure source. For example, a single piston
pump may be used to create over-pressure for dispensing and
under-pressure for aspirating. By using valves establishing
selectively a fluid connection to a high-pressure side or a
low-pressure side of a rotary pump, single pressure source may be
the pressurizing pressure source as well as the suctioning pressure
source. Alternatively, a pressure tank and a vacuum tank may be
provided as separate pressurizing pressure source and as suctioning
pressure source, respectively.
[0009] The pipetting device comprises a gas flow connection between
said connection opening and said at least one pressure source.
[0010] The pipetting device comprises a flow restriction defining
at least a section of said gas flow connection. This way, the flow
restriction divides the gas flow connection in an upstream section
and a downstream section with respect to the flow restriction. The
flow restriction defines a flow resistance for the gaseous medium
crossing the flow restriction.
[0011] The pipetting device comprises a first sensor configured to
measure a quantity indicative of the temperature of the flow
restriction. This first sensor may e.g. be an electrical resistor
having an electrical resistance depending on the temperature, as
e.g. an PT-100 or a PT-1000 resistor. In this case, the quantity is
the electrical resistance. This quantity can be converted into a
temperature value. The first sensor, in the previous example the
resistor, is mounted in proximity or in thermal contact to the flow
restriction, such that the temperature of the resistor always stays
close to the temperature of the walls of the flow resistance, which
walls are in contact with the gaseous medium.
[0012] The inventors have recognized that the temperature of the
flow resistance in a pipetting device of the kind described,
significantly influences the amount of gaseous working medium
passing the flow restriction per time. Surprisingly, with the help
of the first sensor, the amount of gaseous working medium passing
the flow resistance per time can be predicted with significantly
increased accuracy. This leads in turn to higher accuracy in the
liquid volumes pipetted by driving a liquid by means of the gaseous
working medium.
[0013] The inventors have noticed that a similar accuracy cannot be
achieved by keeping the temperature of the inflowing gaseous medium
constant or by measuring the temperature of the gaseous medium
before it reaches the flow restriction and using this measured
temperature to predict the amount of gaseous working medium passing
the flow resistance per time.
[0014] Embodiments of the pipetting device according to the
invention are defined by features recited in claims 2 to 10.
[0015] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the embodiments still
to be addressed unless in contradiction, the pipetting device
further comprises a time controller operatively connected to a
controllable valve, which controllable valve is configured to
selectively open or interrupt the gas flow connection in a
time-controlled manner.
[0016] The inventors have recognized that with the increased
precision reached in predicting the amount of gaseous working
medium passing the flow resistance per time, an open loop control
of the opening time of the gas flow connection is sufficient to
achieve acceptable precision in the pipetted volumes. This is
particularly useful for pipetting volumes in the range of 0.1
microliters to 5000 microliters. A relative precision (Coefficient
of Variation, CV) of pipetted volumes below 10 microliters of 2.5%
CV or lower, in particular of 0.5% or lower, is achievable with the
present invention for a pipetting volume of 10 to 5000 microliters.
The closing signal can be sent to the controllable valve purely
based on the time elapsed and without any need to wait for measured
signals, e.g. from a flow sensor, to be evaluated. The opening time
of the controllable valve may be calculated in advance, i.e. before
sending the opening signal to the controllable valve.
[0017] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the pipetting device further comprises a heat
storage block, wherein the flow restriction is formed by an inner
wall of the heat storage block or wherein the flow restriction is
formed by a flow restriction element embedded in the heat storage
block, and wherein the first sensor is a temperature sensor
thermally connected to the heat storage block.
[0018] The inventors have recognized that a pipetting device
comprising a heat storage block as defined above, displays
increased temporal stability of the pipetted volumes. In
particular, systematic drifts of the deviation between a requested
volume and an effectively pipetted volume in a longer pipetting
sequence are avoided by surprisingly simple means.
[0019] In one alternative of the embodiment, an inner wall of the
heat storage block directly forms the flow restriction. E.g. a hole
drilled directly into the heat storage block may form the flow
restriction. This alternative has the advantage that the inner wall
is thermally well connected to the heat storage block. For higher
flow rates, where very small diameters of the flow restriction are
not needed, this alternative may be the solution to choose.
[0020] In a second alternative of the embodiment, a flow
restriction element separate from the heat storage block may form
the flow restriction. The flow restriction element, which may e.g.
be a capillary, is embedded into the heat storage block. This
second alternative has the advantage that a flow restriction of
very small inner diameter or cross section may be achieved by using
a prefabricated flow restriction element. For very low flow rates,
highest precision may be achieved according to this second
alternative.
[0021] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the heat storage block comprises a metal, in
particular wherein the heat storage block comprises sintered metal,
in particular, wherein the heat storage block consists of a
monolithic sintered metal structure.
[0022] The heat storage block of this embodiment effectively
protects the flow restriction against temperature fluctuations
stemming from the ambient or from neighboring elements of the
pipetting device. Specifically, a monolithic sintered metal
structure further allows for a very compact design even with curved
channels inside the heat storage block. It may be produced by an
additive manufacturing technology, such as e.g. laser sintering of
a metal powder. This embodiment provides a heat storage block with
high specific heat capacity in combination with high thermal
conductivity.
[0023] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the flow restriction is formed by an inner wall
of the heat storage block and the inner wall is the wall of at
least a section of a through hole through the heat storage block,
in particular of a through hole formed by mechanical drilling,
formed by laser drilling or formed by an additive manufacturing
method.
[0024] This embodiment implements the first alternative for
establishing a flow restriction in a heat storage block as
discussed above. The flow restriction may be formed by the complete
through hole along its full length across the heat storage block.
The flow restriction may be formed by a narrow section of a through
hole across the heat storage block. In the latter case, sections of
the through hole upstream or downstream of the fluid restriction
may have larger cross-section, such that the narrow section mainly
determines the flow resistance of a fluid flowing through the
through hole.
[0025] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the flow restriction is formed by a flow
restriction element embedded in the heat storage block, wherein a
wall of the flow restriction element consists of a first material
having a first specific thermal conductivity, wherein the heat
storage block consists of a second material having a second
specific thermal conductivity, and wherein the second specific
thermal conductivity is higher than the first specific thermal
conductivity.
[0026] This embodiment implements the first alternative for
establishing a flow restriction in a heat storage block as
discussed above. In this alternative, the flow restriction element
is an element different from the heat storage block and consists of
a material different from the material of the heat storage block.
The wall of the flow restriction element or the complete flow
restriction element may e.g. consist of glass, such as e.g. fused
silica. The first thermal conductivity may then be in the range of
0.1 Wm.sup.-1K.sup.-1 to 10 Wm.sup.-1K.sup.-1. The second specific
thermal conductivity may be in the range of 10 Wm.sup.-1K.sup.-1 to
1000 Wm.sup.-1K.sup.-1, in particular in the range of 100
Wm.sup.-1K.sup.-1 to 1000 Wm.sup.-1K.sup.-1. To achieve this, the
heat storage block may e.g. be made of a metal or a metal alloy,
such as stainless steel, copper or bronze. The values of the
specific thermal conductivities given above are for 25.degree. C.
The material of the flow restriction element may be selected such
that a processing method may be applicable to the flow restriction
element, which is not applicable to the heat storage block
directly.
[0027] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the flow restriction element is formed as a
tubular capillary, in particular a glass capillary, in particular
made from fused silica. The tubular capillary extends through a
cavity formed in the heat storage block.
[0028] Pulling a tubular capillary is a processing method
applicable to glass, in particular to fused silica, and leads to
precisely controllable inner diameters even at small inner
diameters in the range below 0.5 mm, in particular below 0.2 mm. In
this diameter range, mechanical drilling is not precise enough. As
the inventors have recognized, the combination of features of this
embodiment solves the problem of reproducibly producing a fluid
restriction of small cross-section with high precision and at the
same time avoiding negative impact on pipetting precision via
temperature variations of the gaseous working medium.
[0029] In an example of the previously discussed embodiment, an
inner surface of the cavity is arranged such that thermal radiation
can be exchanged with an outer surface of the tubular capillary.
Alternatively, or in combination with the previous example, an
inner surface of the cavity is in thermally conducting contact with
an outer surface of the tubular capillary. Alternatively, or in
combination with one of the previous examples, the cavity is
partially or completely filled with a material having a specific
thermal conductivity of at least the specific thermal conductivity
of said tubular capillary. In particular, the cavity may be filled
with thermally conducting glue.
[0030] The exchange of thermal radiation may e.g. simply take place
across a volume containing air. This volume may be free of
obstacles for thermal radiation, such as solid elements. The inner
wall of the cavity may surround the outer surface of the tubular
capillary in all direction or nearly all direction. The tubular
capillary may be glued to the heat storage block. The glue provides
thermal conducting contact in addition to the possibility of
exchange of thermal radiation. The glue may further provide a fluid
tight gasket.
[0031] As another example, the cavity may be partially or
completely filled with a glue, in particular with a glue having
high thermal conductivity. A glue having high thermal conductivity
is, as an example, an epoxy with one of the following fillers:
aluminum oxide, aluminum nitride, silver or graphite.
[0032] The inventors have recognized that the accuracy and
precision with this embodiment are particularly high. In this
embodiment, the temperature of the flow restriction tends to stay
close to the temperature of the heat storage block.
[0033] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the pipetting device comprises a multiplicity of
connection openings, the pipetting device comprises a multiplicity
of gas flow connections between each of said connection openings
and the at least one pressure source, and the pipetting device
comprises a multiplicity of flow restrictions each defining at
least a section of one of said gas flow connections of said
multiplicity of gas flow connections. All of the flow restrictions
of said multiplicity of flow restrictions are embedded in the heat
storage block.
[0034] In one embodiment of the pipetting device according to the
invention, which may be combined with any of the preaddressed
embodiments and any of the embodiments still to be addressed unless
in contradiction, the heat storage block further accommodates at
least an electrically operated valve, in particular a controllable
valve of the embodiments comprising at least a controllable
valve.
[0035] The inventors have recognized that surprisingly, high
precision and accuracy of the pipetted volumes can be achieved,
when electrically operated valves of the pipetting device are
accommodated in the heat storage block. This is surprising, as
electrically operated valves are a source of temperature drift, as
their temperature increases with the number switching operations.
In addition, the longer electrically operated valves are open, i.e.
the larger the volumes to be pipetted are, the more heat is
produced. Typically, opening of the valve is associated with a
current flowing through a magnetic coil in the valve, which current
produces heat, whereas the valve is closed by a spring element,
such that no heat is produced in the closed state of the valve.
Bringing the electrically operated valve in close proximity of the
flow restriction reduces dead volumes in the path of the gaseous
working fluid. Surprisingly, a negative side effect on precision
and accuracy of the pipetted volumes due to temperature drift
induced by the electrically operated valves is avoided by the means
proposed by the present invention. High thermal conductivity of the
heat storage block and high heat capacity of the heat storage block
are beneficial, as both properties stabilize the temperature of the
heat storage block. Increasing the specific heat capacity of the
material of the heat storage block or the mass of the heat storage
block, or both, increases the heat capacity of the heat storage
block.
[0036] The invention is further directed to a gas flow connection
element according to claim 11. The gas flow connection element
according to the invention is a gas flow element for a pipetting
device according to embodiments of the invention, which comprise a
heat storage, and wherein the first sensor is a temperature sensor
thermally connected to the heat storage block. It combines
essential features of these embodiments in a single element, which
may be provided as an exchangeable spare part for a pipetting
device.
[0037] The gas flow element comprises the flow restriction.
[0038] The gas flow element comprises the heat storage block into
which the flow restriction is embedded or wherein the flow
restriction is formed by an inner wall of the heat storage
block.
[0039] The gas flow element comprises the temperature sensor being
thermally connected to the heat storage block and/or to the flow
restriction.
[0040] Further in the scope of the invention lies a method of
pipetting a liquid volume of a liquid according to claim 12. The
inventive method is a method of pipetting a liquid volume of a
liquid by driving said liquid by means of a gaseous working medium.
The method comprises the steps of
a) providing a pipetting device according to the invention; b)
defining a volume of liquid to be pipetted and defining whether
pipetting is aspirating or dispensing; c) reading a value from the
first sensor; d) determining a temperature of the flow restriction
as function of at least the value read from the first sensor; e)
determining at least one pipetting parameter as a function of the
volume of liquid to be pipetted and of the temperature determined
in step d); f) operating the pipetting device by applying the at
least one pipetting parameter determined in step e), which
operating involves flowing of an amount of the gaseous working
medium across the flow restriction, thereby pipetting the liquid
volume.
[0041] The method makes best use of the pipetting device according
to the invention.
[0042] Variants of the method are defined by features recited in
claims 13 to 15.
[0043] In one variant of the method according to the invention,
which may be combined with any of the variants still to be
addressed unless in contradiction, the pipetting device used in the
method is a pipetting device according an embodiment, which further
comprises a time controller operatively connected to a controllable
valve, which controllable valve is configured to selectively open
or interrupt said gas flow connection in a time-controlled manner.
According to this variant of the method, at least one pipetting
parameter determined in step e) is an opening time of the
controllable valve, and
[0044] operating the pipetting device comprises the partial
steps
f1) starting pipetting of the liquid volume by opening the at least
one valve during the opening time determined in step e); and f2)
closing the controllable valve after the opening time has
elapsed.
[0045] In one variant of the method according to the invention,
which may be combined with any of the variants involving an opening
time of a controllable valve, the opening time is controlled by
open-loop control.
[0046] This variant of the method is particularly suitable to
achieve very small volumes of pipetted liquid.
[0047] In a further variant of the method according to the
invention, which may be combined with any of the variants involving
an opening time of a controllable valve, the opening time is
determined further in function of at least one of [0048] an ambient
temperature, [0049] an ambient pressure, [0050] calibration data
indicative for a switching time of the controllable valve, [0051] a
parameter or a set of parameters defining a geometric property of
the flow restriction, in particular a cross section area of the
flow restriction, a length of the flow restriction, or a flow
resistance of the flow restriction for a fluid having a defined
viscosity, a temperature dependence of the viscosity of the gaseous
working medium.
[0052] Further parameters in addition to the quantity indicative of
the temperature of the flow restriction, which can be measured by
the first sensor of the pipetting device, may be used as input in a
computational model simulating the behavior of the gaseous working
medium in the flow restriction. The computational model may e.g. be
run on a microprocessor used for control of the pipetting device.
With this, the volume of gaseous working medium passing the flow
restriction per time may be predicted even with higher precision.
The parameter or a set of parameters defining a geometric property
of the flow restriction may for example be determined in a
calibration procedure, wherein the volume flow through a flow
restriction to be calibrated is compared a volume flow through a
volume flowing through a flow restriction standard under equal
conditions.
[0053] The invention shall now be further exemplified with the help
of figures. The figures show:
[0054] FIG. 1 shows a schematic view of the pipetting device
according to the invention;
[0055] FIG. 2 shows a schematic view of an embodiment of the
pipetting device;
[0056] FIG. 3 shows a schematic view of a further embodiment of the
pipetting device;
[0057] FIG. 4a shows a schematic view of a gas flow connection
element according to the invention;
[0058] FIG. 4b, FIG. 4c, FIG. 4d each show a cross-section through
different examples of an embodiment of the gas flow element;
[0059] FIG. 5 shows a perspective view of a heat storage block;
[0060] FIG. 6 shows a flow chart of the method of pipetting a
liquid volume of a liquid according to the invention.
[0061] FIG. 1 shows schematically and simplified, a pipetting
device 10 according to the invention. To illustrate its
functionality, the present view shows in addition to the pipetting
device itself some further elements in a specific pipetting
situation. The pipetting device is shown with a pipette 21 attached
to the connection opening 14 of the pipette connector 13. The
pipette shown in this view contains a liquid, which at the moment
is set under pressure by a gaseous working volume entering through
the connection opening 14 into the pipette 21. A drop of liquid is
pushed out of an opening of the pipette opposite to the opening of
the pipette, which is in connection with the connection opening of
the pipetting device. A previously produced liquid volume 22 is
situated in one of the wells 23 of a well plate arranged below the
pipette tip.
[0062] The gaseous working medium is pressurized by the pressure
source 11. A gas flow connection leads from the pressure source 11
across a flow restriction 15 to the pipette connector and thus
establishes connection from the pressure source 11 to the
connection opening 14, through which the gaseous working medium can
flow. A first sensor 16 is configured to measure a quantity
indicative of the temperature .theta. of the flow restriction. The
first sensor 16 is in close proximity of the flow restriction 15. A
measuring device and possible a calculation device may be
operatively connected to the first sensor 16.
[0063] FIG. 2 shows a schematic view of an embodiment of the
pipetting device. In addition to the elements already discussed in
the context of FIG. 1, this embodiment comprises a controllable
valve 18. The controllable valve 18 is operatively connected to a
time controller 17, wherein the operative connection is indicated
by a dashed line. The controllable valve is arranged in the gas
flow connection, in the example shown here in the upstream part of
the gas flow connection with respect to the flow restriction. The
controllable valve 18 is configured to selectively open or
interrupt the gas flow connection 12 in a time-controlled manner.
The controllable valve may e.g. be a magnetic valve, which is
normally held in a closed state by means of a spring and can be
opened by applying an electric current to a coil, the timing of the
electrical current being controlled by the time controller 17. In
this example, the operative connection between the time controller
17 and the controllable valve may be provided by a pair of
electrically conducting wires.
[0064] FIG. 3 shows a schematic view of a further embodiment of the
pipetting device. The pipetting device shown here comprises a
positive pressure source 11' and a negative pressure source 11'',
each of which is built as pressure tank. The flow connection 12 to
the pipette connector branches into two arms, one leading to the
positive pressure source, the other leading to the negative
pressure source. The branching is in the upstream section with
respect to the flow restriction 15. A two-way valve 18' and a
two-way valve 18'' are provided in each of the two arms. A third
valve, being a switching valve 18''' allows to selectively connect
the first arm of the flow connection to either the positive
pressure source 11' or to reference pressure 30, e.g. atmosphere
pressure. All three valves 18', 18'', 18''' mentioned above are
operatively connected to a time controller 17, as indicated by
dashed lines. The first two-way valve 18' and the switching valve
18'' in combination form a controllable discharge valve
arrangement. The first two-way valve 18' and the second two-way
valve 18'' are both controllable valves being configured to
selectively open or interrupt said gas flow connection 12 in a
time-controlled manner. The flow restriction 15 is arranged in the
flow connection 12. A first sensor 16 is configured to measure a
quantity indicative of the temperature of the flow restriction
15.
[0065] In partial FIG. 4a a schematic view of a gas flow connection
element 20 according to the invention and in partial FIGS. 4b, 4c
and 4d cross-sections through possible realization of the gas flow
connection element 20 shown schematically in FIG. 4a. The gas flow
connection element 20 comprises a heat storage block 19, into which
the flow restriction 15 is embedded. All partial FIGS. 4a to 4d
show embodiments comprising a heat storage block 19, such that the
elements shown in these partial figures may be seen as the
respective part of a pipetting device according to one of the
above-mentioned embodiments comprising a heat storage block. A
first sensor 16, which in this case is a temperature sensor, is
thermally connected to the heat storage block 19. A first section
of the gas flow connection 12 is shown immediately adjacent to the
flow restriction 15 in FIG. 4a. These sections may be coupled in a
releasable way to further sections of the gas flow connection 12 in
a complete pipetting device. In the embodiment shown in FIG. 4b a
cavity 41 is formed into the heat storage block 19. Tubular
capillary extends across the cavity and is glued at opposite ends
to the heat storage block. Glue 42 provides thermally conducting
contact between an outer surface of the tubular capillary and the
heat storage block and further seals a gap between the heat storage
block and the tubular capillary, such that gas flow is forced
through the narrow inner bore of the capillary forming the flow
restriction element 15'. The inner surface of the cavity 41 is
arranged around the capillary and without radiation blocking
elements between them, such that thermal radiation can be exchanged
between an outer surface of the tubular capillary and the inner
surface of the cavity. The first sensor 16 being a temperature
sensor is positioned at the end of a blind hole formed into the
heat storage block at a position closer to the inner walls of the
cavity than to an outer surface of the heat storage element. The
heat storage element may e.g. comprise metal or may be made of
metal.
[0066] In the example embodiment shown in FIG. 4c, there is no
separate flow restriction element, but the flow restriction 15 is
rather formed by an inner wall of the heat storage block. A middle
section of the through hole 43 is narrower than an inlet and an
outlet section of the through hole and forms the flow restriction.
A temperature sensor 16 is mounted in close proximity of the
section forming the flow restriction 15. In the further example
embodiment shown in FIG. 4d, a flow restriction element in the form
of a capillary is present. The flow restriction element 15' is
embedded in a cavity 41, which is partially filled with a thermally
conductive glue 44. A temperature sensor 16 is embedded in the
thermally conductive glue 44 and sits in close proximity to the
flow restriction element 15'. In the embodiment shown, the distance
from the temperature sensor 16 to the capillary is less than the
diameter of the capillary. As illustrated at the left end of the
capillary, an additional sealing element may be arranged between
the capillary and the heat storage element 19 in order to insure
that the gaseous working medium flows through the flow restriction
element 15', which in this case has the form of a capillary.
[0067] FIG. 5 shows a perspective view of an embodiment of a heat
storage block 19. The heat storage block shown provides through
holes for accommodating four flow restriction elements 15'. The
four flow restriction elements 15' are shown in a position offset
in the axial direction towards the openings visible in the current
view. In their finally mounted position, the flow restriction
elements 15' may not be visible from the viewpoint used in this
figure. The final mounting position of the restriction elements may
correspond to the situations illustrated in FIG. 4b or 4d, such
that the flow restriction elements are well protected by the
surrounding heat storage block. Two arrows indicate possible
positions of two temperature sensors 16. The temperature sensors
may e.g. be mounted on a printed circuit board, which may be
arranged on a surface of the heat storage block. The embodiment of
the heat storage block shown here provides structures for holding a
printed circuit board, which is not shown, in place. Two
temperature sensors allow to determine a mean temperature of the
heat storage block as well as to detect the presence of a
temperature gradient across the heat storage block. With this
sensor configuration, the temperature of each of the four flow
restriction elements 15' can be determined with even higher
precision. The temperature sensors and possibly further sensor, as
e.g. pressure sensors or differential pressure sensor may be
arranged on a print, for which a cutout is foreseen. A heat storage
block with complicated geometry as shown here may be produced as a
monolithic sintered metal structure, e.g. by laser sintering a
metal powder or a similar additive production method. These
production methods allow for non-straight holes inside the heat
storage block. The inventors have recognized that such an
arrangement leads to a very compact design and very little dead
volumes in the gas flow connection element 20 and in the pipetting
device 10 according to the invention.
[0068] FIG. 6 shows a flow chart of the method 100 of pipetting a
liquid volume of a liquid. Begin and end of the method are marked
with START and END. In the variant of the method shown in this
figure, steps 101 to 106 corresponding to the steps a) to f) are
executed one after the other, step 101 being the first step and
step 106 being the last step. According to the inventive method,
some of the steps may overlap or partially overlap in time. Steps
which do not depend on the result of another step may be executed
in a different order, e.g. step b) (step 102) and step c) (step
103) may be exchanged, as reading a value from said first sensor 16
is independent of the defining of a volume to be pipetted. Step c)
may even be performed continuously in parallel to the other steps
of the method. In a specific variant of the method, wherein the at
least one pipetting parameter determined in step e) is an opening
time .DELTA.t of the controllable valve, the last step 106
comprises partial steps 107 and 108 denoted as f1) and f2),
namely
f1) starting 107 pipetting of the liquid volume by opening said at
least one valve during the opening time determined in step e); and
f2) closing 108 the controllable valve after the opening time
.DELTA.t has elapsed.
LIST OF REFERENCE SIGNS
[0069] 10 pipetting device [0070] 11 pressure source [0071] 11'
pressurizing pressure source [0072] 11'' suctioning pressure source
[0073] 12 gas flow connection [0074] 13 pipette connector [0075] 14
connection opening [0076] 15 flow restriction [0077] 15' flow
restriction element [0078] 16 first sensor [0079] 17 time
controller [0080] 18, 18', 18'', 18''' controllable valve [0081] 19
heat storage block [0082] 20 gas flow connection element [0083] 21
pipette [0084] 22 liquid volume [0085] 23 well [0086] 30 reference
pressure [0087] 41 cavity (formed in the heat storage block) [0088]
42 glue [0089] 43 through hole [0090] 44 thermally conductive glue
[0091] 100 method of pipetting a liquid volume [0092] 101 step a)
of the method [0093] 102 step b) of the method [0094] 103 step c)
of the method [0095] 104 step d) of the method [0096] 105 step e)
of the method [0097] 106 step f) of the method [0098] 107 partial
step f1) [0099] 108 partial step f2) [0100] p+ positive pressure
[0101] p- negative pressure [0102] .DELTA.t opening time of
controllable valve [0103] .theta. temperature of the flow
restriction [0104] .theta..sub.a ambient temperature [0105] p.sub.a
ambient pressure [0106] .eta. viscosity of gaseous working
medium
* * * * *